MRI is a nuclear magnetic resonance technique that finds application, in the field of diagnostics, to visualize and distinguish between different tissues or organs in the human or animal body through the spatial localization of water protons.
Several MRI contrast agents are known in the art among which is a paramagnetic MRI contrast agent named as gadobenate dimeglumine salt, also referred to as GdBOPTA-Dimeg (MultiHance®, by Bracco Imaging S.p.A).
For a general reference to GdBOPTA-Dimeg see, as an example, EP-A-230893, Invest. Radiol., (1990), 25/Suppl. 1), S59-S60; and C. de Haen et al. Journal of Computer Assisted Tomography 1999, 23 (Suppl. 1):S161-168.
Gadobenate dimeglumine is a paramagnetic MRI contrast agent wherein the paramagnetic gadolinium ion is complexed by BOPTA, a chelating agent forming a highly stable coordinating sphere around the gadolinium ion Gd (III), further salified with N-methylglucamine, this latter also referred to as meglumine.
This MRI contrast agent is characterised, over other known gadolinium complexes, with relaxivity properties that make it particularly advantageous in the field of diagnostics.
It is indicated, as an example, for the detection of focal liver lesions in patients with known or suspected primary liver cancer (e.g. hepatocellular carcinoma) or metastatic diseases.
In addition, it is also indicated for the MRI of the central nervous system in adults, to visualize lesions with abnormal blood brain barrier or abnormal vascularity of the brain, spine and associated tissues.
The ligand coordinating the gadolinium ion, commonly named as BOPTA, is 4-carboxy-5,8,11-tris(carboxymethyl)-1-phenyl-2-oxa-5,8,11-triazamidecan-13-oic acid, having the following formula (I):

The synthesis of the chelating agent BOPTA of formula (I) may be represented according to the scheme below:

This synthesis comprises, essentially, a selective monoalkylation of diethylenetriamine (DETA) with 2-chloro-3-phenylmethoxy propionic acid, in the presence of water and at a temperature of 50° C., followed by isolation and resin purification of the resulting compound, so as to get N-[2-[(2-aminoethyl)amino]ethyl]-O-(phenylmethyl)serine of formula (II), as the hydrochloride salt.
In the subsequent step, the intermediate (II) is carboxymethylated with bromoacetic acid in water, at a temperature of 50° C. and at pH 10. The resulting crude is then isolated and, after purification through resins, affords the solid compound of formula (I), BOPTA, with a resulting overall yield of 21%.
For a general reference to the above synthetic process and operative conditions thereof see, as an example, EP-A-230893 and Inorg. Chem., 1995, 34(3), 633-42.
According to an improved process, the international patent application WO 00/02847 discloses the preparation of BOPTA from DETA, comprising the alkylation of this latter with 2-chloro-3-(phenylmethoxy)propionic acid potassium salt.
The subsequent carboxymethylation reaction step of the intermediate (II) with bromoacetic acid is carried out at basic pH, and at a temperature of 55° C.
Bromoacetic acid, in particular, is slowly added to the aqueous solution of the precursor of formula (II), for instance present as alkaline carboxylate salt, whilst maintaining the pH values within the range of 11-12 through the addition of a base.
The above operative conditions allow to complete the reaction so as to lead to the compound of formula (I) whilst avoiding an excessive formation of undesired byproducts.
At lower pH levels, in fact, the formation of quaternary ammonium salts may compete with the formation of the desired final compound of formula (I).
On the other side, higher pH values during the carboxymethylation step do require larger amounts of bromoacetic acid due to the competition of hydroxy (OH−) groups towards bromine substitution. Furthermore, at higher pH values degradation of the benzyloxypropionic moiety can occur.
By varying the pH conditions, therefore, considerable amounts of by-products may be obtained during the course of the reaction, thus leading to a remarkable decrease in terms of yields of the process and degree of purity of the final compound (I).
Hence, because of the sensitivity of the reaction to pH values, the above carboxymethylation step of WO 00/02847 is carried out by properly dosing the addition of both reactants, that is of bromoacetic acid and of the base, so as to get and maintain the desired basic pH values during the whole course of the reaction.
Typically, on an industrial scale, means are known to suitably dose reactants affecting the pH reaction environment such as, for instance, the use of pH meters.
With the aim of avoiding the formation of the aforementioned byproducts, therefore, pH meters could be used to control and drive the addition of bromoacetic acid and of the base in the above carboxymethylation reaction.
However, as minor variations of pH might lead to the preparation of the final compound in lower yields, because of the formation of relevant amounts of by-products and impurities, any inaccurate electrode pH measurement, whenever used to control the addition of the above reactants, would certainly represent a remarkable drawback and limitation.
In this respect, it would be of utmost importance the need for pH electrodes which provide affordable pH measurements during the whole course of the reaction, under the above operative conditions of temperature and alkalinity.
The above requirement for an accurate and reliable pH measurement of the reaction medium could be even more important in the case of large amounts of sodium ions, for instance due to the use of sodium hydroxide, which presence is known to interfere with pH electrode measurement.